In this case of hypobetalipoproteinemia (HBL), differential diagnoses for genetic and secondary HBL are provided. Several additional issues can be noted.
This patient also had an IgA paraproteinemia, which can influence cholesterol concentrations. Monoclonal paraproteinemia can hinder lipoprotein clearance, thereby increasing circulating cholesterol while artifactually lowering cholesterol measurements (1). This patient's cholesterol concentrations were lower than those typically observed with heterozygous genetic HBL, raising the question of paraprotein interference or another unidentified heterozygous mutation influencing apolipoprotein B (apo B) concentrations. Perhaps another familial variant was in play in the death of the proband's son at age 21 years.
Familial hypocholesterolemia has received recent attention with the identification of mutations in the ANGPTL32 (angiopoietin-like 3) and PCSK9 (proprotein convertase subtilisin/kexin type 9) genes as novel causes of low cholesterol concentrations (2). Like HBL-associated apo B variants, ANGPTL3 and PCSK9 mutations appear well tolerated and potentially atheroprotective, features that are generating therapeutic interest in these targets. Similarly, inhibiting APOB transcription via the use of antisense oligonucleotides is in late-stage therapeutic development. Ongoing attempts to lower apo B concentrations despite the success of statins and other cholesterol-lowering medications (e.g., ezetimibe, bile acid sequestrants, niacin) reflect many clinical issues: statin intolerance, high baseline cholesterol concentrations, the lowering of LDL goals, and the increasing identification of familial hypercholesterolemia and its treatment challenges.
↵2 Human genes:
- angiopoietin-like 3;
- proprotein convertase subtilisin/kexin type 9.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
- Received for publication February 22, 2012.
- Accepted for publication February 28, 2012.
- © 2012 The American Association for Clinical Chemistry